Analysis of the structural effects of HIV-1 maturation inhibitors

Wednesday, October 26, 2011 — Poster Session IV
2:00 p.m. – 4:00 p.m.	Natcher Conference Center	NIAMS	VIROL/MICRO-10

Authors

• P Keller
• C Adamson
• B Heymann
• K Waki
• E Freed
• A Steven

Abstract

Retroviral maturation, involving cleavage of the polyprotein Gag into its components, MA (matrix), CA (capsid), SP1 (spacer) and NC (nucleocapsid) by the viral protease (PR), is essential for retroviral infectivity. Maturation inhibitors, defined by the compound bevirimat (BVM), are a new class of HIV-1 antivirals that block viral replication by inhibiting the final PR cleavage event, preventing separation of the CA and SP1 domains of Gag. Evidence suggests that direct interaction of BVM with assembled Gag prevents PR from accessing the CA/SP1 cleavage site. In order to examine the mechanism of action of BVM, we have analyzed the three-dimensional structure of BVM-treated HIV-1 by cryo-electron tomography. We found that these particles contain an incomplete remnant of the immature Gag lattice that appears to be stabilized by the drug. We observed core-like structures in many cleavage-inhibited particles, indicating that the free fraction of CA protein remains capable of mature assembly. We conclude that the morphology of BVM-treated virions represents incomplete maturation of CA protein combined with stabilization of the immature lattice. We are currently analyzing HIV-1 samples treated with a novel maturation inhibitor, PF-46396, in order to compare with BVM-treated virus, revealing the common features of maturation inhibitor mechanisms of action.

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